Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof-of-concept study

T-cells; Ibrutinib; DNA loadCélulas T; Ibrutinib; Carga de ADNCèl·lules T; Ibrutinib; Càrrega d'ADNIt is unknown whether Torque Teno virus (TTV) DNA load monitoring could anticipate the development of infectious events in hematological patients undergoing treatment with small molecular targeting agents. We characterized the kinetics of plasma TTV DNA in patients treated with ibrutinib or ruxolitinib and assessed whether TTV DNA load monitoring could predict the occurrence of Cytomegalovirus (CMV) DNAemia or the magnitude of CMV-specific T-cell responses. Multicenter, retrospective, observational study, recruiting 20 patients treated with ibrutinib and 21 with ruxolitinib. Plasma TTV and CMV DNA loads were quantified by real-time PCR at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment inception. Enumeration of CMV-specific interferon-γ (IFN-γ)-producing CD8+ and CD4+ T-cells in whole blood was performed by flow cytometry. Median TTV DNA load in ibrutinib-treated patients increased significantly (p = 0.025) from baseline (median: 5.76 log10 copies/mL) to day +120 (median: 7.83 log10 copies/mL). A moderate inverse correlation (Rho = −0.46; p < 0.001) was found between TTV DNA load and absolute lymphocyte count. In ruxolitinib-treated patients, TTV DNA load quantified at baseline was not significantly different from that measured after treatment inception (p ≥ 0.12). TTV DNA load was not predictive of the subsequent occurrence of CMV DNAemia in either patient group. No correlation was observed between TTV DNA loads and CMV-specific IFN-γ-producing CD8+ and CD4+ T-cell counts in either patient group. The data did not support the hypothesis that TTV DNA load monitoring in hematological patients treated with ibrutinib or ruxolitinib could be useful to predict either the occurrence of CMV DNAemia or the level of CMV-specific T-cell reconstitution; nevertheless, due to the small sample size, further studies involving larger cohorts are warranted to elucidate this issue.Estela Giménez (Juan Rodés Contract, JR18/00053) and Eliseo Albert (Juan Rodés Contract; JR20/00011) hold contracts funded by the Carlos III Health Institute (co-financed by the European Regional Development Fund, ERDF/FEDER). This research was supported by a grant from FIS PI18/00127 (Fondo de Investigaciones Sanitarias), Ministerio de Sanidad y Consumo, Spain)

Análisis de Restricciones a través del Software Arena. Caso Empresa de Fabricación de Calzado

In all production process, it is necessary to know the restrictions that prevent a normal performance of them. Due which the question arises. How to identify the restrictions present in a shoe assembly process.? For this reason, in this paper, a digital model of the shoe assembly process will be built and analyzed using the Arena® software tool, in a company at Barranquilla city. 10 replications of the simulation of the process will be carried out during 30 days, taking into account that only 8 hours are worked during 6 days each week. The results obtained show that the operators remain occupied for more than 90% of the time, therefore, certain recommendations were presented to improve the processes. One of them was to add a new operator in that section. With which, the average waiting times in the process will be reduced. It was concluded that, through the simulation of processes, the moments in which restrictions occur can be identified, which will allow offering alternatives for continuous improvement and greater productivity in any company.En todo proceso productivo es necesario conocer las restricciones que impiden un normal desempeño de los mismos. Por lo cual surge la pregunta. ¿Cómo identificar las restricciones presentes en un proceso de ensamblaje de calzado? Por tal motivo, en este trabajo se construirá y analizará un modelo digital del proceso de ensamble de calzado utilizando la herramienta de software Arena®, en una empresa de la ciudad de Barranquilla. Se realizarán 10 réplicas de la simulación del proceso durante 30 días, teniendo en cuenta que solo se trabajan 8 horas durante 6 días cada semana. Los resultados obtenidos muestran que los operarios permanecen ocupados más del 90% del tiempo, por lo que se presentaron ciertas recomendaciones para mejorar los procesos. Una de ellas fue agregar un nuevo operador en esa sección. Con lo cual, se reducirán los tiempos promedio de espera en el proceso. Se concluyó que, a través de la simulación de procesos, se pueden identificar los momentos en los que se presentan las restricciones, lo que permitirá ofrecer alternativas de mejora continua y mayor productividad en cualquier empresa

BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study

Producción CientíficaMale breast cancer (MBC) is a rare disease that represents <1 % of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7 %), 95.9 % with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations

Combining multivariate statistics and the think-aloud protocol to assess Human-Computer Interaction barriers in symptom checkers

[EN] Symptom checkers are software tools that allow users to submit a set of symptoms and receive advice related to them in the form of a diagnosis list, health information or triage. The heterogeneity of their potential users and the number of different components in their user interfaces can make testing with end-users unaffordable. We designed and executed a two-phase method to test the respiratory diseases module of the symptom checker Erdusyk. Phase I consisted of an online test with a large sample of users (n = 53). In Phase I, users evaluated the system remotely and completed a questionnaire based on the Technology Acceptance Model. Principal Component Analysis was used to correlate each section of the interface with the questionnaire responses, thus identifying which areas of the user interface presented significant contributions to the technology acceptance. In the second phase, the think-aloud procedure was executed with a small number of samples (n = 15), focusing on the areas with significant contributions to analyze the reasons for such contributions. Our method was used effectively to optimize the testing of symptom checker user interfaces. The method allowed kept the cost of testing at reasonable levels by restricting the use of the think-aloud procedure while still assuring a high amount of coverage. The main barriers detected in Erdusyk were related to problems understanding time repetition patterns, the selection of levels in scales to record intensities, navigation, the quantification of some symptom attributes, and the characteristics of the symptoms. (C) 2017 Elsevier Inc. All rights reserved.This work was supported by Helse Nord [grant HST1121-13], the Faculty of Health Sciences from UIT The Arctic University of Norway [researcher code 1108], and The Research Council of Norway [grant 248150/O70]. We thank Professor Emeritus Rafael Romero-Villafranca for reviewing the statistical analysis of this paper.Marco-Ruiz, L.; Bones, E.; De La Asuncion, E.; Gabarron, E.; Aviles-Solis, JC.; Lee, E.; Traver Salcedo, V.... (2017). Combining multivariate statistics and the think-aloud protocol to assess Human-Computer Interaction barriers in symptom checkers. Journal of Biomedical Informatics. 74:104-122. https://doi.org/10.1016/j.jbi.2017.09.002S1041227

Análisis de Restricciones a través del Software Arena. Caso Empresa de Fabricación de Calzado

In all production process, it is necessary to know the restrictions that prevent a normal performance of them. Due which the question arises. How to identify the restrictions present in a shoe assembly process.? For this reason, in this paper, a digital model of the shoe assembly process will be built and analyzed using the Arena® software tool, in a company at Barranquilla city. 10 replications of the simulation of the process will be carried out during 30 days, taking into account that only 8 hours are worked during 6 days each week. The results obtained show that the operators remain occupied for more than 90% of the time, therefore, certain recommendations were presented to improve the processes. One of them was to add a new operator in that section. With which, the average waiting times in the process will be reduced. It was concluded that, through the simulation of processes, the moments in which restrictions occur can be identified, which will allow offering alternatives for continuous improvement and greater productivity in any company.En todo proceso productivo es necesario conocer las restricciones que impiden un normal desempeño de los mismos. Por lo cual surge la pregunta. ¿Cómo identificar las restricciones presentes en un proceso de ensamblaje de calzado? Por tal motivo, en este trabajo se construirá y analizará un modelo digital del proceso de ensamble de calzado utilizando la herramienta de software Arena®, en una empresa de la ciudad de Barranquilla. Se realizarán 10 réplicas de la simulación del proceso durante 30 días, teniendo en cuenta que solo se trabajan 8 horas durante 6 días cada semana. Los resultados obtenidos muestran que los operarios permanecen ocupados más del 90% del tiempo, por lo que se presentaron ciertas recomendaciones para mejorar los procesos. Una de ellas fue agregar un nuevo operador en esa sección. Con lo cual, se reducirán los tiempos promedio de espera en el proceso. Se concluyó que, a través de la simulación de procesos, se pueden identificar los momentos en los que se presentan las restricciones, lo que permitirá ofrecer alternativas de mejora continua y mayor productividad en cualquier empresa

Restrictions analysis using software arena. case shoe manufacturing company

En todo proceso productivo es necesario conocer las restricciones que impiden un normal desempeño de los mismos. Por lo cual surge la pregunta. ¿Cómo identificar las restricciones presentes en un proceso de ensamblaje de calzado? Por tal motivo, en este trabajo se construirá y analizará un modelo digital del proceso de ensamble de calzado utilizando la herramienta de software Arena®, en una empresa de la ciudad de Barranquilla. Se realizarán 10 réplicas de la simulación del proceso durante 30 días, teniendo en cuenta que solo se trabajan 8 horas durante 6 días cada semana. Los resultados obtenidos muestran que los operarios permanecen ocupados más del 90% del tiempo, por lo que se presentaron ciertas recomendaciones para mejorar los procesos. Una de ellas fue agregar un nuevo operador en esa sección. Con lo cual, se reducirán los tiempos promedio de espera en el proceso. Se concluyó que, a través de la simulación de procesos, se pueden identificar los momentos en los que se presentan las restricciones, lo que permitirá ofrecer alternativas de mejora continua y mayor productividad en cualquier empresa.In all production process, it is necessary to know the restrictions that prevent a normal performance of them. Due which the question arises. How to identify the restrictions present in a shoe assembly process.? For this reason, in this paper, a digital model of the shoe assembly process will be built and analyzed using the Arena® software tool, in a company at Barranquilla city. 10 replications of the simulation of the process will be carried out during 30 days, taking into account that only 8 hours are worked during 6 days each week. The results obtained show that the operators remain occupied for more than 90% of the time, therefore, certain recommendations were presented to improve the processes. One of them was to add a new operator in that section. With which, the average waiting times in the process will be reduced. It was concluded that, through the simulation of processes, the moments in which restrictions occur can be identified, which will allow offering alternatives for continuous improvement and greater productivity in any compan

The impact of virus population diversity on the dynamics of cytomegalovirus DNAemia in allogeneic stem cell transplant recipients

Mixed cytomegalovirus (CMV) infections are associated with delayed viral clearance in solid organ transplant recipients. We investigated whether this could be extrapolated to allogeneic stem cell transplant (allo-SCT) recipients. A total of 48 plasma specimens, obtained during 29 episodes of active CMV infection in 25 non-consecutive allo-SCT patients, were analysed. Baseline blood specimens, drawn shortly prior to the inception of pre-emptive antiviral therapy (pre-treatment specimen; n=29), as well as follow-up samples obtained either after the initiation of antiviral therapy (post-treatment specimen; n=15) or during recurrent episodes (n=4) were analysed. Plasma CMV DNA loads were quantified by real-time PCR and the CMV genotyping was performed by ultra-deep sequencing of hypervariable regions in the genes coding for glycoproteins N (gN) and O (gO). A trend towards higher CMV DNA peak loads, longer CMV DNAemia episode durations and slower CMV DNAemia decay rates was observed for episodes with mixed CMV genotype populations compared to those caused by single CMV variants, although the differences did not reach statistical significance. The length of the treatment course required to clear DNAemia was significantly longer in these mixed episodes (P=0.002). Significant changes in the number or frequency of CMV gN or gO genetic variants were documented following the initiation of antiviral therapy or in recurrent episodes. CMV diversity may have a major impact on the kinetics of CMV DNAemia clearance during the treatment of active CMV infection episodes in allo-SCT recipients.The study was supported by grants from the FIS [Healthcare Research Fund (Fondo de Investigaciones Sanitarias in the original Spanish), the Ministry of Health and Consumer Affairs, Spain] (FIS 12/01992), the Ministry of Economy and Competitiveness [MINECO (Ministerio de Economía y Competitividad in the original Spanish)] (BFU2014-58656-R) and the Valencian Regional Government (PROMETEO/2016/122).Peer reviewe

Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: A single-centre retrospective comparative study.

A subgroup of patients with SARS-CoV-2 infection was thought to have developed cytokine release syndrome and were treated with tocilizumab; however, a significant percentage of patients evolved. This study aimed to determine the usefulness of anakinra as a rescue treatment for patients with tocilizumab-refractory COVID-19 disease. A prospective cohort of patients with COVID-19 pneumonia who received anakinra as salvage therapy after failure of tocilizumab were compared (1:1) with selected controls in a historical cohort of patients treated with tocilizumab. Cases and controls were matched by age, comorbidities, pulse oximetry oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio at baseline, and time elapsed since the initiation of treatment with tocilizumab. The primary outcome was the improvement in clinical status measured by a 6-point ordinal scale, from baseline to day 21. The study included 20 cases and 20 controls (mean age 65.3 ± 12.8 years, 65% males). No differences were found in the clinical improvement rates at 7, 14 and 21 days of follow-up. The in-hospital mortality rate for patients receiving anakinra was 55% vs. 45% in the control group (P = 0.527). Treatment with anakinra was not useful in improving the prognosis of patients with tocilizumab-refractory severe COVID-19.This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COV20/00181) — co‐financed by European Development Regional Fund “A way to achieve Europe”. M.F.R. holds a research contract “Miguel Servet” (CP18/00073) from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III.S

Suitability of Two Rapid Lateral Flow Immunochromatographic Assays for Predicting SARS-CoV-2 Neutralizing Activity of Sera

Purpose: Assessment of commercial SARS-CoV-2 immunoassays for their capacity to provide reliable information on sera neutralizing activity is an emerging need. We evaluated the performance of two commercially-available lateral flow immunochromatographic assays (LFIC) (Wondfo SARS-CoV-2 Antibody test and the INNOVITA 2019-nCoV Ab test) in comparison with a SARS-CoV-2 neutralization pseudotyped assay for COVID-19 diagnosis in hospitalized patients, and investigate whether the intensity of the test band in LFIC associates with neutralizing antibody (NtAb) titers. Patients and Methods: Ninety sera were included from 51 patients with moderate to severe COVID-19. A green fluorescent protein (GFP) reporter-based pseudotyped neutralization assay (vesicular stomatitis virus coated with SARS-CoV-2 spike protein) was used. Test line intensity was scored using a 4-level scale (0 to 3+). Results: Overall sensitivity of LFIC assays was 91.1% for the Wondfo SARS-CoV-2 Antibody test, 72.2% for the INNOVITA 2019-nCoV IgG, 85.6% for the INNOVITA 2019-nCoV IgM and 92.2% for the NtAb assay. Sensitivity increased for all assays in sera collected beyond day 14 after symptoms onset (93.9%, 79.6%,93.9% and 93.9%, respectively). Reactivities equal to or more intense than the positive control line (≥2+) in the Wondfo assay had a negative predictive value of 100% and a positive predictive value of 96.4% for high NtAb50 titers (≥1/160). Conclusions: Our findings support the use of LFIC assays evaluated herein, particularly the Wondfo test, for COVID-19 diagnosis. We also find evidence that these rapid immunoassays can be used to predict high SARS-CoV-2-S NtAb50 titers.This work was supported by Valencian Government grant IDIFEDER/2018/056 to JRD, Generalitat Valenciana grant Covid_19-SCI to RG-R, Spanish National Research Council grant CSIC-COV19-082 and Fondo Supera Covid-19 grant BlockAce to RG-RN

Inference of SARS-CoV-2 Neutralizing Activity of Sera by using LFIC assays

Assessment of commercial SARS‐CoV‐2 immunoassays for their capacity to provide reliable information on sera neutralizing activity is an emerging need. We evaluated the performance of two commercially‐available lateral flow immunochromatographic assays (LFIC) (Wondfo SARS‐CoV‐2 Antibody test and the INNOVITA 2019‐nCoV Ab test) in comparison with a SARS‐CoV‐2 neutralization pseudotyped assay for COVID‐19 diagnosis in hospitalized patients, and investigate whether the intensity of the test band in LFIC associates with neutralizing antibody (NtAb) titers. Ninety sera were included from 51 patients with moderate to severe COVID‐19. A green fluorescent protein (GFP) reporter‐based pseudotyped neutralization assay (vesicular stomatitis virus coated with SARS‐CoV‐2 spike protein) was used. Test line intensity was scored using a 4‐level scale (0 to 3+). Overall sensitivity of LFIC assays was 91.1% for the Wondfo SARS‐CoV‐2 Antibody test, 72.2% for the INNOVITA 2019‐nCoV IgG, 85.6% for the INNOVITA 2019‐nCoV IgM and 92.2% for the NtAb assay. Sensitivity increased for all assays in sera collected beyond day 14 after symptoms onset (93.9%, 79.6%,93.9% and 93.9%, respectively). Reactivities equal to or more intense than the positive control line (≥2+) in the Wondfo assay had a negative predictive value of 100% and a positive predictive value of 96.4% for high NtAb50 titers (≥1/160). Our findings support the use of LFIC assays evaluated herein, particularly the Wondfo test, for COVID‐19 diagnosis. We also find evidence that these rapid immunoassays can be used to predict high SARS‐CoV‐2‐S NtAb50 titers.This work was supported by Valencian Government grant IDIFEDER/2018/056 to JRD, Generalitat Valenciana grant Covid_19-SCI to RG-R, Spanish National Research Council grant CSIC-COV19-082 and Fondo Supera Covid-19 grant BlockAce to RG-RPeer reviewe